Ethanol is one of the most widely abused substances in the world, yet the molecular mechanisms of action of ethanol is poorly understood. Ethanol has been shown to disrupt ion channel functions in vitro through interactions with hydrophobic domains of channel subunit proteins. It is still unclear, however, how these effects of ethanol relate to the behavioral changes observed in humans and other organisms. Unlike other drugs of abuse, ethanol is likely to act through multiple molecular targets rather than upon a single major neurotransmitter receptor or transporter. We have initiated studies using C. elegans as a model system to understand the neurobiological effects of ethanol. We have shown that C. elegans exhibits similar behavioral responses to ethanol as mammalian systems including acute intoxication, adaptive neural responses or acute tolerance and state-dependency. We propose to isolate mutants that are hypersensitive to the intoxicating effects of ethanol on different behaviors. We have devised screens that provide for the isolation of mutants hypersensitive to the effects of ethanol on locomotory and egg laying behaviors. We will also identify mutants defective in acute tolerance to ethanol and mutants exhibiting enhanced tolerance. A final screen provides for an enrichment in mutants that are insensitive to the state-dependent effects of ethanol. Secondary behavioral characterizations and pharmacological assays will be carried out to determine whether the mutations affect neural activity and whether the phenotypes are likely to be ethanol specific. We will map the mutations to specific chromosomal regions and molecularly characterize many of the mutants. The genes identified are likely to encode relevant targets of ethanol, either as direct targets or as members of a pathway affected by ethanol. The studies should also lead to a greater understanding of the molecular mechanisms mediating the effects of ethanol invertebrate systems. The determination of the mechanisms of action of ethanol should provide the basis for a directed approach to the development of therapeutics to treat alcoholism and alcoholic neurological disorders.